Despite the high incidence of neurological disease in people infected with the human immunodeficiency virus (HIV-1), our understanding of the neuropathogenesis remains limited. Although several reports have demonstrated blood-brain barrier (BBB) alterations in patients with AIDS dementia, the relationships between the development of BBB dysfunction, virus entry to the CNS, and the evolution of pathological changes in the CNS have not been determined because patients generally are examined for such alterations at the end stages of disease. Anti-viral therapy and opportunistic infections of the CNS further complicate studies of HIV-infected individuals. The SIV/macaque model is an excellent system in which to examine the relationship between BBB integrity, CNS viral burden, and the development of neurological disease. SIV produces neurological disease that shares key clinical and pathological features with HIV encephalitis. Furthermore, it is possible to inoculate macaques with molecular cloned and biologically characterized virus and to examine the tissues of the macaque at specific time points after inoculation. Such studies would provide important data on the pathological events that lead to BBB alterations and CNS disease, providing an understanding of the role of pathological changes of the BBB in HIV CNS disease. Our hypothesis is that during natural infection with HIV-1, a neuro- invasive/neurovirulent strain of virus is selected from the macrophage- tropic virus swarm in the CNS (possibly by virtue of its ability to replicate in endothelial cells), and that cytokines produced by infected macrophages induce the expression of cell adhesion molecules on brain endothelium thus promoting the entry of inflammatory cells into the CNS. Further, infection of endothelial cells contributes to a breakdown in BBB integrity leading to further entry of virus-infected cells and contributing to the development of neurological dysfunction. The precise order of these events is not clear nor is it known if replication of a neurovirulent virus in either CNS endothelial or brain macrophages is sufficient to initiate these events. The studies described will address these issues. Aim 1 will determine the nature and extent of BBB changes in rhesus macaques inoculated with neurovirulent SIV and will examine whether alterations of BBB function is associated with increased viral load in the CNS, changes in immune cell trafficking to the CNS and the development of neuropathological lesions. Aim 2 will examine whether early virus entry into the CNS is a result of loss of BBB integrity and/or replication of virus in brain endothelial cells. Aim 3 will examine the molecular basis for neuroinvasiveness/ neurovirulence and the role of neurovirulent SIV in the BBB function and CNS pathogenesis.